A Crucial Role for Ergosterol in Plasma Membrane Composition, Localisation, and Activity of Cdr1p and H-ATPase in .

is an opportunistic fungal pathogen of humans. Treatment of infections relies on azoles, which target the lanosterol 14α-demethylase (Erg11p) encoded by the gene. Our results show that targeted gene disruption of can result in resistance to ergosterol-dependent drugs (azoles and amphotericin B), auxotrophy and aerobically viable cells. Abnormal sterol deposition and lack of ergosterol in the strain leads to reduced plasma membrane (PM) fluidity, as well as dysfunction of the vacuolar and mitochondrial membranes, resulting respectively in defects in vacuole fusion and a reduced intracellular ATP level. The altered PM structure of the strain contributes to delocalisation of H-ATPase and the Cdr1 efflux pump from the PM to vacuoles and, resulting in a decrease in PM potential (Δψ) and increased sensitivity to ergosterol-independent xenobiotics. This new insight into intracellular processes under Erg11p inhibition may lead to a better understanding of the indirect effects of azoles on cells and the development of new treatment strategies for resistant infections.